A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability
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Many molecular details remain to be uncovered concerning the regulation of polyamine metabolism. A previous model of mammalian polyamine metabolism showed that S-adenosyl methionine availability could play a key role in polyamine homeostasis. To get a deeper insight in this prediction, we have built a combined model by integration of the previously published polyamine model and one-carbon and glutathione metabolism model, published by different research groups. The combined model is robust and it is able to achieve physiological steady-state values, as well as to reproduce the predictions of the individual models. Furthermore, a transition between two versions of our model with new regulatory factors added properly simulates the switch in methionine adenosyl transferase isozymes occurring when the liver enters in proliferative conditions. The combined model is useful to support the previous prediction on the role of S-adenosyl methionine availability in polyamine homeostasis. Furthermore, it could be easily adapted to get deeper insights on the connections of polyamines with energy metabolism.
KeywordsMetabolic modeling Systems biology Polyamines S-adenosyl methionine Methionine cycle Folate cycle
Our experimental work is supported by grants PS09/02216, SAF2008-02522 and SAF2011-26518 (Spanish Ministry of Science and Innovation), and PIE P08-CTS-3759, CVI-6585 and funds from group BIO-267 (Andalusian Government). The “CIBER de Enfermedades Raras” is an initiative from the ISCIII (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ARP is the recipient of a FPU Fellowship (Spanish Ministry of Education).
Conflict of interest
The authors have declared no conflict of interest.
- Andrianantoandro E, Basu S, Karig DK, Weiss R (2006) Synthetic biology: new engineering rules for an emerging discipline. Mol Syst Biol 2:2006.0028Google Scholar
- Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A, Cuellar AA, Dronov S, Gilles ED, Ginkel M, Gor V, Goryanin II, Hedley WJ, Hodgman TC, Hofmeyr J-H, Hunter PJ, Juty NS, Kasberger JL, Kremling A, Kummer U, Le Novère N, Loew LM, Lucio D, Mendes P, Minch E, Mjolsness ED, Nakayama Y, Nelson MR, Nielsen PF, Sakurada T, Schaff JC, Shapiro BE, Shimizu TS, Spence HD, Stelling J, Takahashi K, Tomita M, Wagner J, Wang J, Forum S (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:524–531PubMedCrossRefGoogle Scholar
- Jell J, Merali S, Hensen ML, Mazurchuk R, Spernyak JA, Diegelman P, Kisiel ND, Barrero C, Deeb KK, Alhonen L, Patel MS, Porter CW (2007) Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA. J Biol Chem 282:8404–8413PubMedCrossRefGoogle Scholar
- Korhonen VP, Niiranen K, Halmekytö M, Pietilä M, Diegelman P, Parkkinen JJ, Eloranta T, Porter CW, Alhonen L, Jänne J (2001) Spermine deficiency resulting from targeted disruption of the spermine synthase gene in embryonic stem cells leads to enhanced sensitivity to antiproliferative drugs. Mol Pharmacol 59:231–238PubMedGoogle Scholar
- Latasa MU, Boukaba A, García-Trevijano ER, Torres L, Rodríguez JL, Caballería J, Lu SC, López-Rodas G, Franco L, Mato JM, Avila MA (2001) Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration. FASEB J 15:1248–1250PubMedGoogle Scholar
- Le Novère N, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, Demir E, Wegner K, Aladjem MI, Wimalaratne SM, Bergman FT, Gauges R, Ghazal P, Kawaji H, Li L, Matsuoka Y, Villéger A, Boyd SE, Calzone L, Courtot M, Dogrusoz U, Freeman TC, Funahashi A, Ghosh S, Jouraku A, Kim S, Kolpakov F, Luna A, Sahle S, Schmidt E, Watterson S, Wu G, Goryanin I, Kell DB, Sander C, Sauro H, Snoep JL, Kohn K, Kitano H (2009) The systems biology graphical notation. Nat Biotechnol 27:735–741PubMedCrossRefGoogle Scholar
- Martínez-Chantar ML, Latasa MU, Varela-Rey M, Lu SC, García-Trevijano ER, Mato JM, Avila MA (2003) l-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine. J Biol Chem 278:19885–19890PubMedCrossRefGoogle Scholar
- Reyes-Palomares A, Montañez R, Real-Chicharro A, Chniber O, Kerzazi A, Navas-Delgado I, Medina MA, Aldana-Montes JF, Sanchez-Jimenez F (2009) Systems biology metabolic modeling assistant: an ontology-based tool for the integration of metabolic data in kinetic modeling. Bioinformatics 25:834–835PubMedCrossRefGoogle Scholar
- Santamaría E, Muñoz J, Fernandez-Irigoyen J, Sesma L, Mora MI, Berasain C, Lu SC, Mato JM, Prieto J, Avila MA, Corrales FJ (2006) Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases. J Proteome Res 5:944–953PubMedCrossRefGoogle Scholar